glucuronyl-glucosamine-glycan-sulfate and Diabetes-Mellitus--Type-2

Sulodexide is a heterogeneous group of sulfated glycosaminoglycans (GAGs) that is mainly composed of low-molecular-weight heparin. Clinical studies have demonstrated that sulodexide is capable of reducing urinary albumin excretion rates in patients with type 1 and type 2 diabetes, suggesting that sulodexide has renal protection. However, this efficacy remains inconclusive. In this article, we used meta-analysis to summarize the clinical results of all prospective clinical studies in order to determine the clinical efficacy and safety of sulodexide in diabetic patients with nephropathy. Overall, sulodexide therapy was associated with a significant reduction in urinary protein excretion. In the sulodexide group, 220 (17.7%) achieved at least a 50% decrease in albumin excretion rate compared with only 141 (11.5%) in the placebo. The odds ratio comparing proportions of patients with therapeutic success between the sulodexide and placebo groups was 3.28 (95% confidence interval, 1.34-8.06; P=0.01). These data suggest a renoprotective benefit of sulodexide in patients with diabetes and micro- and macroalbuminuria, which will provide important information for clinical use of this drug as a potential modality for diabetic nephropathy, specifically, the prevention of end-stage renal disease that is often caused by diabetes.

Topics: Clinical Trials as Topic; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Glycosaminoglycans; Humans

It has been suggested that sulodexide is able to lower blood pressure (BP). This may be attributed to its ability to restore the endothelial surface layer (ESL). As ESL perturbation is known to be related to the degree of kidney damage, we investigated whether albuminuria, reflecting ESL status, modified the BP-lowering potential of sulodexide.. A post hoc analysis of the double-blind, randomized, placebo-controlled sulodexide microalbuminuria (Sun-MICRO) and macroalbuminuria (Sun-MACRO) studies, including 1056 microalbuminuric and 843 macroalbuminuric subjects with type 2 diabetes receiving maximal tolerated renin-angiotensin-aldosterone system inhibitor therapy, was carried out. We compared the effect of placebo and sulodexide on systolic BP (SBP) among albuminuria groups.. Analysis of covariance, including data from both trials, showed that baseline urine albumin-to-creatinine ratio (UACR) was the only modifier of the SBP response (interaction with treatment P = 0.001). In subjects with an UACR >1000 mg g. The BP-reducing potency of sulodexide is modified by the degree of albuminuria in subjects with type 2 diabetes. As ESL status deteriorates with increasing albuminuria and nephropathy severity, this suggests that ESL restoration may represent a new target for BP treatment in subjects with diabetic nephropathy.

Topics: Albuminuria; Antihypertensive Agents; Blood Pressure; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glycosaminoglycans; Humans; Male; Middle Aged; Severity of Illness Index

To evaluate the effectiveness of sulodexide for the treatment of hard exudates (HE) in non-proliferative diabetic retinopathy (NPDR).. This was a randomized, placebo-controlled, multicenter trial involving 130 patients (65 for each group) who had mild-to-moderate NPDR with macular HE. Participants were given a daily dose of either 50 mg sulodexide or a matching dose of placebo orally for 12 months. Main outcome measure was an improvement in HE defined as a decrease in severity by at least two grades on a 10-grade severity scale. This was evaluated by fundus photography over 12-month period.. The sulodexide group showed significantly greater improvement in HE severity than that shown by the placebo group (39.0 % vs. 19.3 %; chi square, P = 0.005). Logistic regression analysis yielded an odds ratio of 2.790 (95 % confidence interval, 1.155-6.743; P = 0.023) for the effect of treatment once adjustments were made for demographic, prognostic and disease confounders. Intention to treat and per-protocol analysis yielded similar results. Sulodexide's safety was comparable to that of the placebo.. Oral sulodexide therapy over 12 months improved macular HE in patients with mild-to-moderate NPDR, without leading to detectable adverse events. The study protocol was registered on clinicaltrial.gov under identifier NCT01295775.

Topics: Administration, Oral; Aged; Anticoagulants; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Double-Blind Method; Female; Fluorescein Angiography; Glycosaminoglycans; Humans; Male; Middle Aged; Visual Acuity

Glycosaminoglycans or sulodexide has shown benefits in early experimental diabetic nephropathy (DN) models, but its efficacy in patients with early stage of DN is unknown. Methods. Twenty patients were randomly assigned to the placebo group and another 20 patients were randomly assigned to receive sulodexide 100 mg/day for 14 weeks. Primary outcome was a change of urinary TGF-beta1, albuminuria, and glomerular filtration rate (GFR). All patients had stable metabolic profiles for at least 90 days before randomization. Results. Urinary TGF-beta1 increased significantly in the placebo group but did not change significantly in the sulodexide group. Additionally, the mean change of urine TGF-beta1 in the placebo group was significantly higher than that in the sulodexide group (8.44 ± 9.21 versus 2.17 ± 6.96 pg/mg Cr, P = 0.02). Mean changes of urinary albumin were 15.05 ± 30.09 μg/mg Cr (P = 0.038) in the placebo group and 13.89 ± 32.25 μg/mg Cr (P = 0.069) in the sulodexide group. No consistent patterns of side effects were observed. Conclusion. In this 14-week trial, benefits of sulodexide in preventing the increase of urinary TGF-beta1 were observed in patients with normoalbuminuric type 2 diabetes. The study suggests that sulodexide treatment may provide additional renoprotection in early stage DN. This trial is registered with TCTR20140806001.

Topics: Aged; Albumins; Albuminuria; Biomarkers; Body Weight; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Glomerular Filtration Rate; Glycosaminoglycans; Humans; Hypoglycemic Agents; Kidney; Kidney Diseases; Male; Middle Aged; Transforming Growth Factor beta1; Treatment Outcome

The authors studied efficacy of using sulodexide (Vessel Due F) in treatment of patients with clinical class C6 chronic venous disease (CVD) and type 2 diabetes mellitus (DM). The study included a total of sixty-two 18-to-75-year-old patients of both sexes suffering from class C6 CVD and type 2 DM. The patients were randomly assigned to either the Study Group (Group I) and Control Group (Group II) in the ratio of 1:1. The Study Group patients received treatment with sulodexide according to the standard regimen during 50 days. The study included taking case history, examination by a phlebologist and endocrinologist, measuring the malleolar volume, body weight, ultrasound examination of lower-limb vessels, clinical and biochemical blood analyses, coagulogram, planimetry of trophic ulcers, microbiological and cytological study. The primary end point was epithelialization of trophic ulcers after 1 month. Secondary endpoints were ulcer healing after 2 months and dynamic alterations during epithelialization. The Study Group patients as compared to the Control Group patients were found to have statistically significant improvement of the composite index of clinical assessment of VSCC severity, decrease in the malleolar volume, positive dynamics of speed velocity parameters of venous outflow and improvement of quality of life according to the SF-36 questionnaire. After 30 days, epithelialization was achieved in 11 (33.5%) cases in the Study Group and in 6 (19.4%) cases in the Control Group (p<0.05). After 60 days, epithelialization was achieved in 27 (87.1%) and 15 (48.4%) patients of the Study and Control Groups, respectively. The time to complete epithelialization in Group I and II patients amounted to 49.8 ± 1.4 and 76.6 ± 2.4 days, respectively (p<0.05). A conclusion was drawn that administration of sulodexide (Vessel Due F) is effective and pathogenetically substantiated in treatment of patients presenting with class C6 CVD and type 2 DM.. Изучена эффективность применения препарата сулодексид (Вессел Дуэ Ф) при лечении пациентов с хроническими заболеваниями вен (ХЗВ) С6 клинического класса и сахарным диабетом (СД) 2 типа. В исследование включены 62 пациента обоего пола в возрасте от 18 до 75 лет с ХЗВ С6 класса и СД 2 типа. Больные рандомизированы в основную (І) и контрольную (ІІ) группы в соотношении 1:1. Пациенты основной группы получали лечение препаратом сулодексид по стандартной схеме в течение 50 дней. При исследовании производили: сбор анамнеза, осмотр флеболога и эндокринолога, измерение маллеолярного объема, массы тела, ультразвуковое исследование сосудов нижних конечностей, клинический и биохимический анализы крови, коагулограмму, планиметрию трофических язв, микробиологическое и цитологическое исследование. Первичная конечная точка исследования – эпителизация трофических язв через 1 месяц. Вторичные конечные точки – заживление язв через 2 месяца и динамические изменения в процессе эпителизации. В основной группе по сравнению с контрольной выявлены статистически значимое улучшение суммарного показателя по клинической оценке тяжести заболевания VSCC, уменьшение маллеолярного объема, положительная динамика скоростных показателей венозного оттока и улучшение показателей качества жизни по опроснику SF-36. Через 30 дней эпителизация достигнута в 11 (33,5%) наблюдениях в основной и в 6 (19,4%) наблюдениях в контрольной группе (р<0,05). Через 60 дней эпителизация достигнута у 27 (87,1%) и 15 (48,4%) больных в основной и контрольной группах соответственно. Время полной эпителизации у пациентов І и ІІ групп соответственно составило 49,8±1,4 и 76,6±2,4 суток (р<0,05). Сделан вывод, что применение сулодексида (Вессел Дуэ Ф) является эффективным и патогенетически обоснованным при лечении пациентов с ХЗВ С6 класса и СД 2 типа.

Topics: Adult; Aged; Chronic Disease; Cytoprotection; Diabetes Mellitus, Type 2; Drug Monitoring; Endothelium, Vascular; Female; Fibrinolytic Agents; Glycosaminoglycans; Humans; Hypoglycemic Agents; Lower Extremity; Male; Middle Aged; Severity of Illness Index; Treatment Outcome; Ultrasonography, Doppler, Duplex; Vascular Diseases

Sulodexide, a mixture of naturally occurring glycosaminoglycan polysaccharide components, has been reported to reduce albuminuria in patients with diabetes, but it is unknown whether it is renoprotective. This study reports the results from the randomized, double-blind, placebo-controlled, sulodexide macroalbuminuria (Sun-MACRO) trial, which evaluated the renoprotective effects of sulodexide in patients with type 2 diabetes, renal impairment, and significant proteinuria (>900 mg/d) already receiving maximal therapy with angiotensin II receptor blockers. The primary end point was a composite of a doubling of baseline serum creatinine, development of ESRD, or serum creatinine ≥6.0 mg/dl. We planned to enroll 2240 patients over approximately 24 months but terminated the study after enrolling 1248 patients. After 1029 person-years of follow-up, we did not detect any significant differences between sulodexide and placebo; the primary composite end point occurred in 26 and 30 patients in the sulodexide and placebo groups, respectively. Side effect profiles were similar for both groups. In conclusion, these data do not suggest a renoprotective benefit of sulodexide in patients with type 2 diabetes, renal impairment, and macroalbuminuria.

Topics: Aged; Albuminuria; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Female; Glycosaminoglycans; Humans; Hypoglycemic Agents; Male; Middle Aged; Treatment Failure

Sulodexide, a heterogenous group of sulfated glycosaminoglycans, includes low-molecular-weight heparin (~80% ± 8%), high-molecular-weight heparin (~5% ± 3%), and dermatan (~20% ± 8%), with a mean molecular weight of ~9 kDa. The drug is absorbed orally and has no anticoagulant effect in the doses used. Small preliminary studies consistently showed sulodexide to be associated with decreased albuminuria in patients with diabetes.. We conducted a multicenter placebo-controlled double-blinded study to determine the effect of sulodexide on urine albumin excretion in patients with type 2 diabetic nephropathy.. Patients with type 2 diabetes and urine albumin-creatinine ratios (ACRs) of 35-200 mg/g in men and 45-200 mg/g in women were enrolled. Serum creatinine level was <1.5 mg/dL. Blood pressure goal was 130/80 mm Hg. A maximum US Food and Drug Administration-approved dose of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker for a minimum of 4 months before randomization was required.. The study drug was sulodexide, 200 mg/d.. The primary end point was normoalbuminuria (ACR <20 mg/g and a decrease >25%) or 50% decrease in baseline ACR.. In 1,056 randomly assigned patients with a mean baseline ACR of 107.8 ± 83.7 mg/g, comparing the sulodexide versus placebo groups, the primary end point was achieved in 16.5% versus 18.4%; normoalbuminuria, in 7.9% versus 6.1%; and a 50% decrease in albuminuria, in 15.4% versus 17.6%. The relative probability of any given change in albuminuria was identical in both groups.. We were unable to determine whether the administered sulodexide was absorbed from the gastrointestinal tract.. Sulodexide failed to decrease urine albumin excretion in patients with type 2 diabetic nephropathy and microalbuminuria.

Topics: Albuminuria; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Female; Glycosaminoglycans; Humans; Kidney Diseases; Male; Middle Aged

Endothelial glycocalyx perturbation contributes to increased vascular permeability. In the present study we set out to evaluate whether: (1) glycocalyx is perturbed in individuals with type 2 diabetes mellitus, and (2) oral glycocalyx precursor treatment improves glycocalyx properties.. Male participants with type 2 diabetes (n = 10) and controls (n = 10) were evaluated before and after 2 months of sulodexide administration (200 mg/day). The glycocalyx dimension was estimated in two different vascular beds using sidestream dark field imaging and combined fluorescein/indocyanine green angiography for sublingual and retinal vessels, respectively. Transcapillary escape rate of albumin (TER(alb)) and hyaluronan catabolism were assessed as measures of vascular permeability.. Both sublingual dimensions (0.64 [0.57-0.75] μm vs 0.78 [0.71-0.85] μm, p < 0.05, medians [interquartile range]) and retinal glycocalyx dimensions (5.38 [4.88-6.59] μm vs 8.89 [4.74-11.84] μm, p < 0.05) were reduced in the type 2 diabetes group compared with the controls whereas TER(alb) was increased (5.6 ± 2.3% vs 3.7 ± 1.7% in the controls, p < 0.05). In line with these findings, markers of hyaluronan catabolism were increased with diabetes (hyaluronan 137 ± 29 vs 81 ± 8 ng/ml and hyaluronidase 78 ± 4 vs 67 ± 2 U/ml, both p < 0.05). Sulodexide increased both the sublingual and retinal glycocalyx dimensions in participants with diabetes (to 0.93 [0.83-0.99] μm and to 5.88 [5.33-6.26] μm, respectively, p < 0.05). In line, a trend towards TER(alb) normalisation (to 4.0 ± 2.3%) and decreases in plasma hyaluronidase (to 72 ± 2 U/ml, p < 0.05) were observed in the diabetes group.. Type 2 diabetes is associated with glycocalyx perturbation and increased vascular permeability, which are partially restored following sulodexide administration. Further studies are warranted to determine whether long-term treatment with sulodexide has a beneficial effect on cardiovascular risk.. www.trialregister.nl NTR780/ http://isrctn.org ISRCTN82695186. An unrestricted Novartis Foundation for Cardiovascular Excellence grant (2006) to M. Nieuwdorp/E. S. G. Stroes, Dutch Heart Foundation (grant number 2005T037).

Topics: Adult; Albumins; Capillary Permeability; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Endothelium; Endothelium, Vascular; Glycocalyx; Glycosaminoglycans; Humans; Male; Middle Aged; Mouth Mucosa

Urinary albumin excretion frequently persists in diabetic patients who are treated with angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB). Sulodexide, a glycosaminoglycan mixture of 80% heparan sulfate and 20% dermatan sulfate, has been hypothesized to reduce persistent albuminuria. We have conducted a multi-center randomized double-blind pilot study in order to determine the effect of 6 months' therapy with sulodexide on urinary albumin excretion and to address logistical issues for a full-scale trial.. A total of 149 patients with type 2 diabetes and an albumin:creatinine ratio (ACR) between 20 and 300 mg/g were randomized with equal allocation to either placebo, 200 mg of sulodexide or 400 mg of sulodexide. The primary endpoint was the achievement, at 6 months, of either 3(1) return to normoalbuminuria (ACR < 20 mg/g with a decrease of at least 25%) or (2) a decrease in ACR of at least 50% from the baseline value. All patients used a maximum tolerated recommended FDA approved dose of an ACEI or ARB for at least 60 days and had stable blood pressure prior to randomization.. The primary efficacy endpoint was achieved in 25.3% of the patients in the two sulodexide groups combined versus 15.4% of the placebo-treated patients (P = 0.26). The primary endpoint was achieved in 33.3% (P = 0.075 for the comparison to placebo) in the sulodexide 200 mg group and 18.4% (P = 0.781) in the sulodexide 400 mg group. (No consistent patterns of side effects were observed.. Based on the experience gained in this pilot study, one full-scale trial is currently being conducted to evaluate the effects of sulodexide on change in ACR in patients with persistent microalbuminuria, and a longer-term trial is underway to evaluate the effects of sulodexide on long-term renal disease progression in patients with overt proteinuria.

Topics: Aged; Albuminuria; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Chronic Disease; Confidence Intervals; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Glycosaminoglycans; Humans; Hypoglycemic Agents; Male; Middle Aged; Pilot Projects; Probability; Reference Values; Severity of Illness Index; Treatment Outcome; Urinalysis

Diabetic nephropathy may be effectively prevented and treated by controlling glycemia and administering angiotensin-converting enzyme (ACE) inhibitors. However, strict metabolic control can be difficult, and ACE inhibitors may be poorly tolerated and only partially effective, particularly in diabetes mellitus type 2 (DM2), warranting the search for ancillary treatment. Sulodexide is a glycosaminoglycan, a new class of drug that has demonstrated nephroprotective activity in experimental investigations. The Di.N.A.S. study was a randomized, double-blind, placebo-controlled, multicenter, dose-range finding trial to evaluate the extent and duration of the hypoalbuminuric effect of oral sulodexide in diabetic patients. A total of 223 microalbuminuric and macroalbuminuric DM1 and DM2 patients with serum creatinine < or =150 micromol/L and stable BP and metabolic control were recruited. They were randomly allocated to one of four groups: 50 mg/d, 100 mg/d, or 200 mg/d sulodexide daily or placebo for 4 mo (T0 to T4), with 4 mo of follow-up after drug suspension (T4 to T8). Treatment with 200 mg/d sulodexide for 4 mo significantly reduced log albumin excretion rate (logAER) from 5.25 +/- 0.18 at T0 to 3.98 +/- 0.11 at T4 (P < 0.05), which was maintained till T8 (4.11 +/- 0.13; P < 0.05 versus T0). Moreover, the sulodexide-induced percent reductions in AER at T4 were significantly different from the placebo value at T4 and approximately linear to dose increments (30% [confidence limits, 4 to 49%], P = 0.03; 49% [30 to 63%], P = 0.0001; and 74% [64 to 81%], P = 0.0001 in the sulodexide 50, 100, and 200 mg/d groups, respectively. At T8, the sulodexide 200 mg/d group maintained a 62% (45 to 73%) AER significant reduction versus placebo (P = 0.0001). Subanalysis by type of diabetes (DM1 versus DM2, microalbuminuric versus macroalbuminuric, or on concomitant ACE inhibitors versus not on ACE inhibitors) demonstrated similar findings. These effects were obtained without any significant variation in metabolic control and BP or serum creatinine. Very few adverse events were reported; none were serious. In conclusion, a 4-mo course of high doses of sulodexide significantly and dose-dependently improves albuminuria in DM1 and DM2 patients and micro- or macroalbuminuric patients with or without concomitant ACE inhibition. The effect on albuminuria is long-lasting and seemingly additive to the ACE inhibitory effect.

Topics: Administration, Oral; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dose-Response Relationship, Drug; Double-Blind Method; Glycosaminoglycans; Humans

Investigation of sulodexide effects on renal function, hemostasis and lipid metabolism in patients with diabetes mellitus.. 20 diabetics (diabetes mellitus type I and II) received sulodexide (Vessel due F) for 3 weeks. This mixture of low molecular heparin and dermatan sylphate was injected i.m. once a day for 5 days a week with a 2-day interval. Micro- and macro-albuminuria diminished after treatment but further returned to baseline levels. The rate of glomerular filtration, blood levels of glucose and cholesterol, hemostatic parameters remained unchanged. Blood triglycerides fell.. Sulodexide may be useful in pathogenetic treatment of diabetic nephropathy.

Topics: Adult; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Glycosaminoglycans; Hemostasis; Heparin, Low-Molecular-Weight; Humans; Kidney; Lipids; Male; Time Factors

To determine the effect of oral administration of glycosaminoglycans on metabolic control and albumin excretion rate (AER) in NIDDM patients with increased urinary albumin excretion.. Twelve NIDDM hypertensive patients (age 52 +/- 3 years, HbA1c 7.7 +/- 0.2%) on antihypertensive treatment were enrolled in a double-blind placebo-controlled study, assuming either placebo or sulodexide (100 mg/day) for 4 months; at the end of this period, a crossover was performed. We have evaluated routine biochemical parameters plus AER and coagulative function every 2 months.. Both plasma fibrinogen (from 4.15 +/- 0.32 to 2.77 +/- 0.47 mmol/l) and AER (from 128.3 +/- 40.6 to 39.6 +/- 11.9 micrograms/min) decreased significantly after treatment with glycosaminoglycans in respect to placebo; moreover, blood pressure control ameliorated, also in the absence of any variation of therapy.. Glycosaminoglycan therapy, likely in association with a satisfactory control of blood pressure values, seems to prevent the progression of diabetic nephropathy in NIDDM.

Topics: Administration, Oral; Adult; Aged; Albuminuria; Antihypertensive Agents; Blood Glucose; Blood Pressure; Cholesterol; Cholesterol, HDL; Cross-Over Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Female; Glycosaminoglycans; Humans; Hypolipidemic Agents; Male; Middle Aged; Time Factors; Triglycerides

Albuminuria is a dominant biochemical feature of developing diabetic nephropathy. A disturbed metabolism of heparan sulphate characterized by an increased loss of anionic charges in the basement membrane has been considered as one of the main factors causing an increased albumin output into urine. All therapeutic approaches inducing a reduction of the albumin excretion rate (AER) have a protective effect on renal function. The effect of glycosaminoglycan sulodexide on albuminuria was studied in a group of 53 diabetic patients (26 Type 1 and 27 Type 2) with micro and macroalbuminuria. Sulodexide (Vessel Due F) was administered intramuscularly in one daily dose (600 lipasemic units) for 3 weeks followed by a 6 week wash-out period. A significant decrease of AER was found in a total cohort of patients following just 1 week of sulodexide treatment (mean 162 micrograms/min, range 10-2708 micrograms/min vs mean 248 micrograms/min, range 20-3160 micrograms/min, P < 0.001). This effect lasted 3-6 weeks after drug withdrawal. Similar results were obtained if Type 1 and Type 2 diabetic patients were evaluated separately but a delay of the AER reduction was observed in the latter group. In all patients the mean AER was reduced to 60-65% of the initial values. A greater effect of sulodexide on albuminuria was observed in patients with AER above 200 micrograms/min than in those with microalbuminuria (a reduction to 47 vs 65% of the initial output). Sulodexide did not significantly reduce albuminuria in 28% of diabetic patients ('non-responders'). In conclusion, glycosaminoglycan sulodexide may reduce AER in patients with micro or macroalbuminuria and it could slow down development of diabetic nephropathy.

Topics: Adult; Aged; Albuminuria; Blood Glucose; Blood Pressure; Creatinine; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dose-Response Relationship, Drug; Fasting; Female; Glycated Hemoglobin; Glycosaminoglycans; Humans; Hypolipidemic Agents; Male; Middle Aged; Pilot Projects; Serum Albumin; Time Factors

Sulodexide is a promising therapeutic drug for the management of diabetic nephropathy. Although sulodexide has demonstrated a renoprotective effect through its ability to restore glomerular ionic permselectivity, the exact mechanism is still not clear. We investigated the effects of long-term sulodexide treatment on diabetic nephropathy in Otsuka-Long-Evans-Tokushima-Fatty (OLETF) rats.. Diabetic rats were treated with or without sulodexide at 10mg/kg/day in the drinking water for nine months. Renal morphology and changes in VEGF and p38 mitogen-activated protein kinase (p38 MAPK), urinary levels of albumin (UAE) and urinary VEGF excretion were determined. To define the direct effects of sulodexide, we performed an in vitro experiment using podocytes.. UAE was significantly higher in OLETF rats than in control LETO rats, and the sulodexide group showed significantly decreased UAE after six months of treatment. Interestingly, urinary VEGF levels were also significantly decreased in the sulodexide-treated group. In accordance with UAE and urinary VEGF changes, the renal expression of profibrotic molecules was significantly decreased after sulodexide treatment. In addition, the activation of p38 MAPK, assessed by measuring the level of phospho-specific p38 MAPK, increased in diabetic renal tissues and was markedly suppressed by sulodexide treatment. In cultured podocytes, sulodexide treatment significantly decreased high glucose-induced p38 MAPK activation and VEGF synthesis.. Sulodexide directly suppresses VEGF synthesis through the p38 MAPK pathway in podocytes, and these results suggest that sulodexide may provide renoprotection via suppression of renal VEGF synthesis independently of glomerular basement membrane ionic permselectivity in type 2 diabetic rats.

Topics: Animals; Blood Glucose; Blotting, Western; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Glycosaminoglycans; Hypoglycemic Agents; Kidney; Male; Rats; Rats, Inbred OLETF; Vascular Endothelial Growth Factor A

Diabetic nephropathy (DN) is the most serious, life limited complication of both types of diabetes mellitus. Therefore the early identification and intensive treatment of DN is very important. DN involves the thickening of glomerular basement membrane (GBM) and the depletion of glycosaminoglycan (GAG) in the GBM with resultant diminution in the physiological electrostatic charge barrier. Additional mechanism in pathophysiology of DN is mesangial expansion. Sulodexide is glycosaminoglycan mixture of heparansulfate and dermatan sulfate. We present a 71-year old patient with severe nephrotic syndrome, probably caused by DN. AS patient refused renal biopsy, exact diagnosis of DN could not be confirmed. Since 2000 our patient was treated with sulodexide. More pronounced decrease of proteinuria was proved 1.5 year after the begin of this treatment (from 10.37 g/d to 4.8 g/d) and after 3 years was proteinuria negative.

Topics: Aged; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Glycosaminoglycans; Humans; Nephrotic Syndrome; Proteinuria

Topics: Albuminuria; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Glycosaminoglycans; Humans; Kidney Diseases; Male